Current molecular pharmacology最新文献

Background: This study was performed to evaluate the protective effects of chrysin (CH) on metabolic impairment and pancreatic injury caused by sub-chronic chlorpyrifos (CPF) intoxication in male rats.

Methods: Forty male Wistar rats were randomly allocated into five groups (n=8). Intraperitoneal injections of chrysin (12.5, 25 and 50 mg/kg for 45 days) and CPF (10 mg/kg for 45 days) gavage were performed. Present findings indicated that the serum levels of glucose, total cholesterol, and lowdensity lipoprotein-cholesterol, as well as body weight, were increased in the CPF-exposed group.

Results: It was also found that CPF decreased superoxide dismutase activity as well as increased malondialdehyde and nitric oxide levels in the pancreatic tissue of exposed animals. Histopathological examination also confirmed the toxic effects of CPF on pancreatic tissue as mostly evidenced by infiltration of inflammatory cells and necrosis. CH (50 mg/kg) decreased blood glucose concentration (p < 0.05), TG (p < 0.05), and LDL-C in CPF-exposed animals. CH decreased the pancreas levels of MDA in all treated CPF-exposed groups versus the non-treated CPF-exposed group (p < 0.05, p < 0.001, p < 0.001, respectively). A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. A significant difference was not seen in the NO and MDA levels and SOD activity between CHtreated (50 mg/kg) animals exposed to CPF and controls.

Conclusion: A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. In conclusion, CH could prevent initiate and progress of CPF-induced metabolic impairment by modulating oxidative stress in pancreatic tissue as a target organ of organophosphorus pesticides.

Background and objective: The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously via continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 versus the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.

Introduction: CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging via maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82.

Methods: We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.

Result: Our data cast significant doubt that the mechanism of action of E7386 is via specific CBP/β-catenin antagonism.

Conclusion: It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.

Background: This study investigated the role and potential mechanisms of Discoidin domain receptors-1 (DDR1) during liver fibrogenesis.

Methods: Blood and livers were collected from mice. In the in vitro experiments, human normal hepatocyte (LO2 cell line) and human hepatoma cells (HepG2 cell line) with overexpressed DDR1 (DDR1-OE) or DDR1 knockdown (DDR1-KD) were constructed by transfecting the corresponding lentivirus. Human hepatic stellate cells (LX2 cell line) were incubated with a conditioned medium (CM) of the above stable transfected cells treated with collagen. The cells and supernatants were collected for molecular and biochemical analyses.

Results: DDR1 expression was increased in hepatocytes from carbon tetrachloride (CCL4)-induced fibrotic livers compared to normal livers in wild-type (WT) mice. Liver fibrosis was relieved, and hepatic stellate cells (HSC) activation was decreased in CCL4-treated DDR1 knockout (DDR1-KO) mice compared with CCL4-treated WT mice. LX2 cells cultured in CM of LO2 DDR1-OE cells revealed increased α-smooth muscle actin (αSMA) and type I collagen (COL1) expressions and cell proliferation. Meanwhile, cell proliferation and the expression levels of αSMA and COL1 in LX2 cells cultured in CM of HepG2 DDR1-KD cells were decreased. Moreover, IL6, TNFα, and TGFβ1 in CM of DDR1-OE cells appeared to promote LX2 cell activation and proliferation, regulated by NF-κB and Akt pathways.

Conclusion: These results indicated that DDR1 in hepatocytes promoted HSC activation and proliferation and that paracrine factors IL6, TNFα, and TGFβ1 induced by DDR1 through activating NF-κB and Akt pathways may be the underlying mechanisms. Our study suggests that collagen-receptor DDR1 may be a potential therapeutic target for hepatic fibrosis.

Brucellosis is an infectious disease caused by different species of Brucella bacteria. It is also known as Malta fever, one of the neglected diseases that can cause infection in both animals and humans. Although human-to-human infection is rare, it can spread through the inhalation of airborne agents, and if left untreated, it can lead to serious health complications. In this review, we aim to highlight the pathophysiology, prevention, epidemiology, mitigation, cure, targets for drug development, and vaccine development against human brucellosis. Human brucellosis is mainly caused by consuming unpasteurized milk or dairy products, uncooked meat, and contact with infected animals. Human brucellosis outbreaks are mainly associated with developing and low- to middle-income countries. Brucella is present all over the world, and only some of the regions are at high risk, including Asia, Africa, Eastern Europe, Mexico, South and Central America, the Caribbean, the Mediterranean Basin, and the Middle East. Because of intracellular survival, inhibition of apoptosis, and immune evasion, Brucella can survive and multiply inside the host cell, which can cause chronic disease. By using proteomics approaches, several new drug targets were reported for human brucellosis that can be used for the development of novel drugs. We can also develop an efficient vaccine against human brucellosis by exploring previously reported vaccine candidates against animal brucellosis. The information provided through this review will facilitate research to control and cure human brucellosis and its complicated symptoms.

Apelin and its receptor are expressed in many tissues and play an important role in maintaining the homeostasis of the cardiovascular system and body fluids. Also, the association of this system with many diseases, such as diabetes, hypertension, obesity, cancer, diabetic retinopathy, etc., has been determined. This system is considered a therapeutic goal in many mentioned diseases. G protein-coupled receptors (GPCRs) have the ability to form oligomers and dimers with themselves and other receptors. The formation of these oligomers is associated with a change in the signaling pathways of the receptors. Research on the oligo and dimers of these receptors can revolutionize the principles of pharmacology. The apelin receptor (APJ) is also a GPCR and has been shown to have the ability to form dimers and oligomers. This article discusses the dimerization and oligomerization of this receptor with its own receptor and other receptors, as well as the signaling pathways.

Osteosarcoma is the most common primary bone malignancy and has a high tendency of local invasion. Although a lot of studies have focused on chemotherapy and combination chemotherapy regimens in recent years, still, there is no particularly perfect regimen for the treatment of relapsed or metastatic OS, and the prognosis is still relatively poor. As a new therapeutic method, targeted therapy provides a new scheme for patients with osteosarcoma and has a wide application prospect. This article reviews the latest progress of targeted therapy for osteosarcoma, and summarizes the research on the corresponding targets of osteosarcoma through six major pathways. These studies can pave the way for new treatments for osteosarcoma patients who need them.